In the last decades, mesoporous nanoparticles have been a topic of intense research because of the many potential applications that can be developed by taking advantage of their high surface area. Actually, these nanoparticles present pores sizes between 2 to 50 nm (and are thus called ‘mesoporous’ according to IUPAC nomenclature), an ideal characteristic in all those applications where a high surface interaction is essential, for example in biomedical applications (e.g. drug delivery or imaging), in the catalysis and filtration (e.g. heavy metals ion sequestration), in sensor devices (e.g. gas sensor) or in cosmetics, just to name a few application fields. Indeed, the presence of pores in the mesoporous range allows the nanoparticles to be loaded with organic molecules such as enzymes, active substances or inorganic nanometric phases having catalytic, magnetic or optical properties. Normally, mesoporosity of the nanoparticle is intimately associated with an amorphous structure because a crystalline structure generally leads to the closure of the pores.
The intense research in the recent years has been substantially devoted to achieve an increasingly better control of the particles at a micro and nano level, and particularly of their physical-chemical and electronic properties. This goal represents the starting point for developing new materials with highly selective functions, or new multifunctional materials, which are able to meet the requirements of different applications e.g. in nanomedicine. This quest in turn encourages research for oxides which can be synthesized in the form of mesoporous nanoparticles.
Among the oxides, silica have been mainly used so far because the synthesis of stable mesoporous silica nanoparticles (or MSNs) is relatively ease to achieve: a process for synthesizing MSNs based on the sol-gel technique was first developed in Japan in 1990 and later at the Mobil Corp. Laboratories in the US.
Other metal oxide compositions of mesoporous nanoparticles have been described extensively in both the scientific and patent literature such as titanium oxide, yttrium oxide, barium oxide as well as several mixed oxides. For example, Fu and Watson in US20130122298 describes a process for synthesizing a titanium oxide in the form of spherical nanoparticles mesoporous with a diameter between 20-100 nm. In the patent application US20140170088A1 it is disclosed a process for synthesizing nanoparticles of barium oxide and zirconium BaZrO3/BaCO3 useful in the formulation of coatings for biomedical applications. However such methods are not useful to produce zirconia nanoparticles. Often, the metal oxides nanoparticles already known to the state-of-the-art have a low surface to volume ratio, or a low surface electrical charge, or other characteristics which make them not suitable in many applications especially in the biomedical field. This represents a significant drawback that encourages the search for new compositions and consequently for synthesis processes. However, taking aside silica, it is definitely not a simple task the synthesis of metal oxides mesoporous well-separated nanoparticles with a controlled shape and size. The main challenge to overcome is controlling the reactivity of certain intermediates or metal oxides precursors used in the process.
In the present case, the properties of zirconium oxide (or zirconia) nanoparticles, have been described extensively in both the scientific papers and patents. However, nanoparticles known in the state-of-the-art have a crystalline structure which make them non-optimal in those applications where the high specific surface area represent a crucial factor, as in drug delivery, in catalysis or in the treatment of water.
Most relevant for assessing the novelty and the inventive step of the present invention are the following three prior-art documents.
The first paper by Chen et al. ‘Facile Synthesis of Monodisperse Mesoporous Zirconium Titanium Oxide Microspheres with Varying Compositions and High Surface Areas for Heavy Metal Ion Sequestration’ (DOI: 10.1002/adfm.201102878) describes mesoporous microspheres of zirconia-titania (ZrO2—TiO2) binary oxides with different TiO2 contents prepared by sol-gel method. Noticeably, the process proposed by Chen et al. allows also to synthesize microspheres of pure zirconia. However, such particles present a crystalline structure (while binary oxides zirconia-titania microspheres are amorphous) and are characterized by a limited surface area. Furthermore, said pure zirconia microspheres are clusters of aggregated distinct entities of about 3.5 nm in size. Finally, in the paper by Chen et al. the microspheres purification step includes calcination at high temperature (i.e. around 600° C.) that degrades the mesoporous structure.
Although this paper describes a remarkable achievement in the field, due to these drawbacks it contains no useful teachings for those skilled in the art for synthesizing mesoporous nanoparticles composed of pure zirconium oxide having the formula ZrO2.
The second relevant paper is ‘Hollow Mesoporous Zirconia Nanocapsules for Drug Delivery’ by Shaoheng Tang et al. (in Adv. Funct. Mater. 2010, 20, 2442-2447), concerns the synthesis of a very special class of nanoparticles called hollow mesoporous zirconia nanocapsule and their use as drug delivery carrier. These nanoparticles have a microstructure constituted by a spherical cavity (larger than 100 nm) delimited by a mesoporous zirconia shell with a thickness of a few nanometers (approximately 15 nm). For this reason, the authors name them ‘hollow nanocapsules’. In the hollow nanocapsule described by Shaoheng Tang et al. the mesoporosity is obviously limited to the thin zirconia shell, since the internal cavity exceeds the superior limit according to the IUPAC mesoporous definition (50 nm).
It is evident that hollow nanocapsules present a totally different structure from particles having a mesoporous structure extending throughout the entire particle volume (and not throughout only the shell). Such particles are named ‘totally-porous’ or ‘totally-mesoporous’ nanoparticles. For the sake of clarity, the present invention relates to ‘totally-porous particles’ and more specifically to ‘totally-porous nanoparticles’.
In the work by Shaoheng Tang et al. nanocapsules fabrication is based on a process which uses Stöber silica spheres coated with a layer of mesoporous zirconia. After a thermal treatment, that is needed to consolidate the zirconia layer, the sacrificial silica core is removed by means of a treatment in NaOH solution so that the capsules are created. It is evident that such method cannot be used to prepare totally porous nanospheres or, more generally, particles without a large internal cavity. In fact, the spherical shape of the hollow nanocapsules is due to the shape of the spherical silica sacrificial template.
Noticeably, the authors remark that the energy dispersive X-ray spectrum (EDX) of the prepared hollow nanocapsules shows a small amount of silica remaining in the porous zirconia shell. The presence of residual silica have a significant impact on the isoelectric point of the nanocapsules and should be avoided.
The peculiar structure of hollow mesoporous zirconia nanocapsule make them suitable as drug carrier because the spherical cavity can accommodate a large amount of drug. However, drug-loading capacity and efficiency depends tightly on the compatibility between the loaded molecules and the particle carrier, and molecules characteristic such as polarity, hydrophobicity, and surface charge distribution as well as charge distribution of the carrier often affect compatibility. For this reason, the loading mechanism in hollow mesoporous zirconia nanocapsule and in totally-mesoporous nanoparticle are completely different: in the first case, the drug are accommodated in the central cavity, whereas, in the latter, the drug is loaded inside the pores where there is a strong interaction with the internal pores surface. Obviously, the loading mechanism affects also the release mechanism of the drug.
Finally, the third relevant document is the US patent 2010/051877, ‘Superficially porous metal oxide particles, methods for making them, and separation devices using them’ in the name of Ta-Chen Wei et al. In this case, the authors disclose superficially porous particles composed of metal-oxide (i.e. silica, alumina, titania or zirconia) and the preparation thereof. Such superficially porous particles comprise; a solid core having a size ranging from about 20% to about 90% of the size of the entire particle; a substantially porous outer shell having ordered pores. Interestingly, the authors remark the difference between ‘totally porous particles’ and ‘superficially porous particles’ and they conclude that the latter are more suitable for chromatography applications.
Therefore, it is clearly out of the scope of the invention preparing ‘totally-mesoporous’ metal-oxide particles as the purpose of the inventors is disclosing a novel core-shell structure, wherein only the shell is porous, suitable for chromatography applications. Furthermore, the inventors claim, but not provide, any example of superficially porous particles made of zirconia. For the aforementioned reasons, it will be apparent to those skilled in the art that similarly to the work by Shaoheng Tang et al., US2010/051877 does not disclose any useful teaching for preparing ‘totally-mesoporous’ zirconia particles and nanoparticles.
To sum up, the main technical problem which has prevented so far the synthesis of mesoporous zirconium oxide nanoparticles is the much higher reactivity of the zirconia organic precursors (alkoxides) compared to those used in the synthesis of mesoporous silica nanoparticle. For this reason, synthesis routes based on sol-gel techniques, which yield zirconia nanoparticle starting from alkoxides, are very unstable and therefore difficult to control. Nevertheless, sol-gel techniques are attractive due to their simple operation and widely available literature.
A second problem in the synthesis of mesoporous zirconia nanoparticles concerns the purification step that is required to remove any residual surfactant or other organic solvents used in the synthesis. Generally, metal-oxide nanoparticles purification involves thermal treatments, e.g. calcination in an oven at high temperature, or washing cycles with strong acids, e.g. hydrochloric acid. The first technique is commonly used for mesoporous silica nanoparticles as the structure of the amorphous silica is stable to calcination temperatures (around 500-600° C.). The second technique, can be used only when the nanoparticles are not dissolved on acid washing. However, these known purification treatments cannot be used to purify amorphous zirconia nanoparticles because in the temperature range required for surfactant degradation, zirconia changes from an amorphous to a crystalline phase, and unfortunately, this phase transition leads to the closure of the pores in the structure. In addition zirconia particles are etched by acid washing.